A vast amount of research reveals that central dopamine (DA) containing systems are neuronal substrates of a broad spectrum of behaviors related to reward-seeking, motivation, and environmental responsivity. Disruption of these behaviors leads to anhedonia, social isolation, and psychomotor retardation that form core symptoms of depression. While there is little debate for a critical role of limbic structures, e.g. amygdala, in the regulation of mood and affect, the role of limbic DA in the pathobiology of depressive illness is not known. Functional imaging studies report involvement of limbic structures in depression, but few have focused on dopaminergic indices. Furthermore, there is a paucity of neurochemical studies of depression that have utilized postmortem brain tissue. Studies using postmortem brain tissue offer much higher anatomical resolution than it is offered by functional imaging. In preliminary studies, we have found lower dopamine transporter (DAT) and up-regulation of D2 receptors in the basal and central nuclei of the amygdala, but not in the other nuclei of this complex region, in major depression as compared to psychiatrically normal controls. These and other findings compel us to examine the possibility that there is diminished DA neurotransmission in subjects diagnosed with major depression (who died of suicide or natural causes). The central hypothesis of this proposal is that subjects with major depression have diminished mesolimbic DA activity that can be revealed by neurochemical abnormalities in discrete regions of the mesolimbic dopaminergic system. These neurochemical measures will be performed in discrete regions of the amygdala, (Aim 1), in the nucleus accumbens (Aim 2), and in the ventral tegmental area (VTA, Aim 3), core limbic regions of the brain. We also hypothesize that a distinct constellation of neurochemical abnormalities within limbic structures is specific for major depression (Aim 4), and will differentiate the pathobiology of major depression from that of suicide or schizophrenia. Groups of subjects to be studied will be: a) subjects with major depression who committed suicide, b) subjects with major depression not dying by suicide, c) sudden death non-psychiatric controls, and d) schizophrenics not dying by suicide. The proposed research will be the first focused investigation of potential abnormalities of limbic DA in major depression utilizing psychiatrically characterized subjects. The research will establish the specificity of neurochemical findings with respect to major depression and with respect to regional brain anatomy. Uncovering the potential role of DA in the pathobiology of depression may lead to advancements in the pharmacological, and possibly genetic, intervention of major depression.